Symmetrical bis(heteroarylmethoxyphenyl)alkylcarboxylic acids as inhibitors of leukotriene biosynthesis

Article abstract of DOI:10.1021/jm000180n

Symmetrical bis(quinolylmethoxyphenyl)alkylcarboxylic acids were investigated as inhibitors of leukotriene biosynthesis and 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid sodium salt (47·Na) met our design parameters for a drug candidate (ABT-080). This compound was readily synthesized in three steps from commercially available diphenolic acid. Against intact human neutrophils, 47·Na inhibited ionophore-stimulated LTB₄ formation with an IC₅₀ = 20 nM. In zymosan-stimulated mouse peritoneal macrophages producing both LTC₄ and PGE₂, 47·Na showed 9000-fold selectivity for inhibition of LTC₄ (IC₅₀ = 0.16 nM) over PGE₂ (IC₅₀ = 1500 nM). Preliminary pharmacokinetic evaluation in rat and cynomolgus monkey demonstrated good oral bioavailability and elimination half-lives of 9 and 5 h, respectively. Pharmacological evaluation of leukotriene inhibition with oral dosing was demonstrated in a rat pleural inflammation model (ED₅₀ = 3 mg/kg) and a rat peritoneal passive anaphylaxis model (LTB₄, ED₅₀ = 2.5 mg/kg; LTE₄, ED₅₀ = 1.0 mg/kg). In a model of airway constriction induced by antigen challenge in actively sensitized guinea pigs, 47·Na dosed orally blocked bronchoconstriction with an ED₅₀ = 0.4 mg/kg, the most potent activity we have observed for any leukotriene inhibitor in this model. The mode of inhibitory action of 47·Na occurs at the stage of 5-lipoxygenase biosynthesis as it blocks both leukotriene pathways leading to LTB₄ and LTC₄ but not PGH₂ biosynthesis. However, 47·Na does not inhibit 5-lipoxygenase catalysis in a broken cell enzyme assay; therefore it is likely that 47·Na acts as a FLAP inhibitor.

Full text of DOI:10.1021/jm000180n

3322
J . Med. Chem. 2000, 43, 3322-3334
Sym m etr ica l Bis(h eter oa r ylm eth oxyp h en yl)a lk ylca r boxylic Acid s a s In h ibitor s
of Leu k otr ien e Biosyn th esis
Teodozyj Kolasa, David E. Gunn, Pramila Bhatia, Anwer Basha, Richard A. Craig, Andrew O. Stewart,
J ennifer B. Bouska, Richard R. Harris, Keren I. Hulkower, Peter E. Malo, Randy L. Bell, George W. Carter, and
Clint D. W. Brooks*
Immunoscience Research, Abbott Laboratories, D41K, R13-4, 1401 Sheridan Road, North Chicago, Illinois 60064
Received April 25, 2000
Symmetrical bis(quinolylmethoxyphenyl)alkylcarboxylic acids were investigated as inhibitors
of leukotriene biosynthesis and 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid sodium salt
(47‚Na ) met our design parameters for a drug candidate (ABT-080). This compound was readily
synthesized in three steps from commercially available diphenolic acid. Against intact human
neutrophils, 47‚Na inhibited ionophore-stimulated LTB4 formation with an IC50 ) 20 nM. In
zymosan-stimulated mouse peritoneal macrophages producing both LTC4 and PGE2, 47‚Na
showed 9000-fold selectivity for inhibition of LTC4 (IC50 ) 0.16 nM) over PGE2 (IC50 ) 1500
nM). Preliminary pharmacokinetic evaluation in rat and cynomolgus monkey demonstrated
good oral bioavailability and elimination half-lives of 9 and 5 h, respectively. Pharmacological
evaluation of leukotriene inhibition with oral dosing was demonstrated in a rat pleural
inflammation model (ED50 ) 3 mg/kg) and a rat peritoneal passive anaphylaxis model (LTB4,
ED50 ) 2.5 mg/kg; LTE4, ED50 ) 1.0 mg/kg). In a model of airway constriction induced by
antigen challenge in actively sensitized guinea pigs, 47‚Na dosed orally blocked bronchocon-
striction with an ED50 ) 0.4 mg/kg, the most potent activity we have observed for any
leukotriene inhibitor in this model. The mode of inhibitory action of 47‚Na occurs at the stage
of 5-lipoxygenase biosynthesis as it blocks both leukotriene pathways leading to LTB4 and
LTC4 but not PGH2 biosynthesis. However, 47‚Na does not inhibit 5-lipoxygenase catalysis in
a broken cell enzyme assay; therefore it is likely that 47‚Na acts as a FLAP inhibitor.
In tr od u ction
asymmetric synthesis was not available to provide cost-
effective drug substance. A medicinal chemistry ap-
proach to this problem was to investigate structural
modifications that offered new analogues with a more
efficient synthetic process. From the previously reported
structure-activity study (SAR),9 variations of the cy-
clohexyl substituent in 3 demonstrated that a lipophilic
group was important for inhibitory potency and there
existed flexibility in the composition and size for this
substituent. Our hypothesis was to create a symmetrical
nonchiral alkoxyiminoalkylcarboxylic acid analogue 4a
or 4b by replacing the cyclohexyl substituent with a
second 2-quinolylmethoxyphenyl substituent. This hy-
pothesis was tested and found to have merit in providing
a new class of symmetrical bis-QMP leukotriene bio-
synthesis inhibitors. The optimization of the biological
properties of this series examined both QMP-iminoxy
carboxylate 4a and QMP-alkyl carboxylate 4b analogues
culminating in the discovery of the clinical development
candidate 47‚Na (ABT-080).
Leukotrienes are biosynthetic products of arachidonic
acid metabolism.1 Antileukotriene therapy in asthma
has been clinically demonstrated both with agents that
inhibit the biosynthesis of leukotrienes or with those
that block the action of cysteinyl leukotrienes at their
receptor.2 Numerous chemical classes of antileukotriene
agents have been studied, but of these very few have
progressed to market approval.3 The cysteinyl leukot-
riene antagonists, zafirlukast and montelukast, and the
5-lipoxygenase inhibitor, zileuton, are registered for the
treatment of asthma. The discovery of five lipoxygenase-
activating protein (FLAP) by Merck scientists led to an
alternative antileukotriene modality.4 The 18-kDa pro-
tein FLAP was found to be necessary for leukotriene
biosynthesis in vivo.5 The design and characterization
of FLAP inhibitors became an important therapeutic
initiative. The 2-quinolylmethoxyphenyl (QMP) ana-
logues, MK-0591 (1)6 and BAY x105 (2)7 (Chart 1), were
shown to block the function of FLAP and demonstrated
efficacy in clinical studies. Our experience in optimizing
the antileukotriene activity of 2-QMP analogues ex-
plored our oxime insertion hypothesis,8 resulting in the
optimized drug candidate (S)-(+)-(E)-2-cyclohexyl-4-(2-
quinolylmethoxy)phenylmethoxyiminopropionic acid (3,
A-93178) as a potent and selective leukotriene biosyn-
thesis inhibitor.9 One of the drawbacks of 3 was the
synthetic requirement for resolution as a process-scale
Ch em istr y
The compounds of this investigation were prepared
by the methods outlined in Schemes 1-9. The proposed
symmetrical bis(4-(2-quinolylmethoxy)phenyl)methoxy-
iminoalkylcarboxylic acid prototypes 10-13 were pre-
pared as shown in Scheme 1. Alkylation of 4,4′-di-
hydroxybenzophenone (5) with 2 equiv of 2-chloromethyl-
quinoline provided 4-(2-quinolylmethoxy)phenyl ketone
(6), which was reduced with NaBH4 to bis(4-(2-quinolyl-
methoxy)phenyl)methanol (7). Mitsunobu reaction10 of
* Corresponding author: Clint D. W. Brooks. Phone: 847-937-0322.
Fax: 847-937-9249. E-mail: clint.brooks@abbott.com.
10.1021/jm000180n CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/09/2000

Bis(heteroarylmethoxyphenyl)alkylcarboxylic Acids
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3323
Sch em e 1
Ch a r t 1. Leukotriene Biosynthesis Inhibitors
(15) followed by treatment with AlBr3 to afford 1,5-bis-
(4-hydroxyphenyl)-3-pentanone, which was bis-alkylated
with 2-chloromethylquinoline to provide 1,5-bis(4-(2-
quinolylmethoxy)phenyl)-3-pentanone (16). Ketone 16
was converted to the corresponding iminoxy acids 18
and 19 as described previously in Scheme 1.
The bis(quinolylmethoxyphenyl)alkyl carboxylate ana-
logues 41-48 were prepared as outlined in Scheme 3.
Application of the literature method for the synthesis
of diphenolic carboxylates11 provided the intermediate
diphenols 25-32 which were alkylated with 2 equiv of
2-chloromethylquinoline to afford the bis(4-(2-quinolyl-
methoxy)phenyl)alkyl carboxylate esters 33-40, which
were subjected to hydrolysis to provide the correspond-
ing bis(4-(2-quinolylmethoxy)phenyl)alkylcarboxylic ac-
ids 41-48.
Oxime insertion into the alkyl substituents repre-
sented by analogues 53-56 and 60-62 was performed
as outlined in Scheme 4. Reduction of the esters 33-39
with LiAlH4 or NaBH4 to alcohols 49-52 followed by
oxime formation as previously described afforded
bis(4-(2-quinolylmethoxy)phenyl)alkoxyiminoalkyl-
carboxylic acids 53-56. Oxidation of 49, 50, and 52
provided the corresponding aldehydes 57-59, which
were reacted with aminoxyacetic acid to give the desired
bis(4-(2-quinolylmethoxy)phenyl)alkylideneaminoxy-
acetic acids 60-62.
The symmetrical bis-QMP ketone 6 was a key inter-
mediate for the preparation of a variety of analogues
as outlined in Scheme 5. Treatment of 6 with dilithium
propiolate followed by alkylation with methyl iodide
gave the ester 63 which was converted by hydrolysis to
the acid 64. Reaction of 6 with Grignard reagents
provided the tertiary alcohols 65-68. Condensation of
alcohols 65-68 with ethyl mercaptoacetate in the
presence of a Lewis acid followed by hydrolysis of the
ester intermediate gave the corresponding bis(4-(2-
quinolylmethoxy)phenyl)alkylthioacetic acids 69-72.
The ketone 6 was also reacted with the dilithium salt
of 3-butyn-1-ol to provide alcohol 73 which was con-
verted to 5,5-bis(4-(2-quinolylmethoxy)phenyl)-5-hydroxy-
3-pentynyl-1-oxyiminopropionic acid (74) as previously
described.
the alcohol 7 with N-hydroxyphthalimide (HONPht)
gave N-phthaloyl-O-(bis(4-(2-quinolylmethoxy)phenyl)-
methyl)hydroxylamine (8), which was then converted to
O-(bis(4-(2-quinolylmethoxy)phenyl)methyl)hydroxyl-
amine (9) by treatment with hydrazine. Condensation
of 9 with the requisite keto acid provided the bis(4-(2-
quinolylmethoxy)phenyl)methoxyiminoalkylcarboxylic ac-
ids 10-13.
The synthesis of 1,5-bis(4-(2-quinolylmethoxy)phenyl)-
3-pentyloxyiminoalkylcarboxylic acids 18 and 19 is
depicted in Scheme 2. Commercially available bis(4-
methoxybenzylidene)acetone (14) was hydrogenated
over PtO2 to give 1,5-bis(4-methoxyphenyl)-3-pentanone
Additional analogues shown in Scheme 6 were pre-
pared from ketone 6 by reaction with ethyl trimethyl-
silylacetate12 to afford 3,3-bis(4-(2-quinolylmethoxy)-
phenyl)acrylic acid ethyl ester (75). The ester 75 was

3324 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
Kolasa et al.
Sch em e 2
Sch em e 3
hydrolyzed to acid 76 or reduced with LiEt3BH to 3,3-
bis(4-(2-quinolylmethoxy)phenyl)-2-propen-1-ol (77). The
alcohol 77 was converted to the oxyiminoalkylcarboxylic
acids 78 and 79 as previously described. Oxidation of
alcohol 77 to the corresponding aldehyde 80 with
Several diphenolic acid derivatives of 31 were pre-
pared as outlined in Scheme 8. A series of 4,4-bis(4-(2-
heteroarylmethoxy)phenylpentanoic acids (94-99) was
prepared by alkylation of 31 with the requisite het-
eroarylmethyl halide. A series of nonsymmetrical de-
rivatives with one QMP group was prepared by treat-
ment of 31 with 1 equiv of 2-chloromethylquinoline to
afford the intermediate 100 which was alkylated by the
requisite heteroarylmethyl halide followed by hydrolysis
to provide the carboxylate analogues 104-106.
Scheme 9 outlines the preparation of 4,4-bis(3-chloro-
4-hydroxyphenyl)pentanoic acid (110) by a sequence of
chlorination of diphenolic acid 23 with NCS, esterifica-
tion to 108 followed by alkylation with 2-chlorometh-
ylquinoline to 109, and then hydrolysis to 110.
13
BaMnO4 in toluene followed by condensation with
aminooxyacetic acid afforded 3,3-bis(4-(2-quinolylmethox-
y)phenyl)-2-propenyl-1-ideneaminoxyacetic acid (81).
Condensation of ketone 6 with aminooxyacetic acid gave
bis(4-(2-quinolylmethoxy)phenyl)methylideneaminoxy-
acetic acid (82).
Spirocyclic QMP analogues were prepared as outlined
in Scheme 7. Reduction of 1,4-cyclohexanedione mono-
ethylene ketal (86) with NaBH4 gave alcohol 87 which
was subjected to the diphenolic acid synthesis to yield
4,4-bis(4-hydroxyphenyl)-1-cyclohexanol (88). Alkylation
of 88 with 2-chloromethylquinoline gave the bis-QMP
intermediate 89 which was transformed into 4,4-bis(4-
(2-quinolylmethoxy)phenyl)-1-cyclohexyloxyiminoalkyl-
carboxylic acids 90 and 91 according to the methods
outlined in Scheme 1. Oxidation of the alcohol 89 with
PCC gave 92 which was condensed with aminooxyacetic
acid to afford 4,4-bis(4-(2-quinolylmethoxy)phenyl)-1-
cyclohexylideneaminoxyacetic acid (93).
Resu lts a n d Discu ssion
We demonstrated an oxime insertion hypothesis that
involved specific placement of an oxime functionality in
an alkyl linker resulting in substantially improved in
vivo potency of various leukotriene biosynthesis inhibi-
tors.8 (E)-(S)-2-Cyclohexyl-4-(2-quinolylmethoxy)phenyl-
methoxyiminopropionic acid (3) was identified as an
optimized leukotriene biosynthesis inhibitor.9,14 Two

Bis(heteroarylmethoxyphenyl)alkylcarboxylic Acids
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3325
Sch em e 4
Sch em e 5
Sch em e 6
cal molecule, thus eliminating the chiral center of 3 and
the requirement for resolution of enantiomers. The first
analogue of this type, 10 (Table 1), had slightly less in
vitro activity in intact human neutrophil than 3 but
suffered a severe loss of in vivo activity, with only 37%
of inhibition at 3 mg/kg, compared to 3 with an ED50
0.4 mg/kg. The methyl-substituted oxime analogue 11
was a closer comparison to 3 and indeed had similar in
vitro potency and was only about 4 times less potent in
vivo. This was a very encouraging result due to the ease
of synthesis for the symmetrical analogue 11 compared
to 3. The -CH2-CH2- homologue 12 was also an
effective inhibitor, comparable to 11. The -CHdCH-
homologue 13 had poor in vivo activity. The chemical
stability of this iminoxyalkyl carboxylate class of com-
pounds was of concern due to the lability of the
functionality with reactivity comparable to that of the
benzyhydryl derivatives.
primary assays were utilized for the SAR screening
studies: in vitro evaluation of inhibition of calcium
ionophore (A-23187)-stimulated LTB4 formation in hu-
man neutrophils15 and in vivo evaluation of leukotriene
inhibition in an ionophore-induced rat pleurisy.16 The
objective of this investigation was to maintain the
biological activity of 3 as a benchmark to create an
analogue that would be more synthetically accessible
on a commercial scale. One simplification concept was
to replace the cyclohexyl group in 3 with the 4-(2-
quinolylmethoxy)phenyl group resulting in a symmetri-
To improve the stability, the iminoxyalkyl carboxylate
function was insulated by ethylene units from the QMP
system as in analogues 18 and 19 (Scheme 2). These
analogues had in vitro inhibitory activity in human
neutrophils with IC50’s of 50 and 40 nM respectively,

3326 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
Kolasa et al.
Sch em e 7
Sch em e 9
170 nM. Their corresponding in vivo potencies had much
greater variability in the rat ionophore-induced pleurisy
model with oral delivery. From this investigation of
alkyl homologues, the pentanoic acid analogue 47 and
the sodium salt 47‚Na had activity comparable to that
of the best iminoxyalkyl carboxylate 11 with the added
advantage of much improved chemical stability. Inser-
tion of the oxime function into the alkyl homologue bis-
QMP template was examined by evaluation of the
iminoxyalkyl carboxylates 53-56 which exhibited sig-
nificantly inferior in vivo activity. The regioisomeric
oxime form as in analogues 60-62 was also examined
and found to be inferior to the simple alkyl carboxylate
analogue 47. Reduction of the carboxylic moiety in 47
to provide the hydroxyl analogue 52 resulted in at least
a 6-fold drop in activity. From this set of bis-QMP
analogues, 47 offered the best inhibitory activity and
favorable stability properties.
Sch em e 8
The SAR study continued with examination of ana-
logues derived from the bis-QMP ketone 6 (Scheme 5).
The propargyl addition analogue 64 showed in vivo
activity, 48% inhibition at 3 mg/kg. The hydroxy ana-
logues 65-67 did not have in vivo activity at the 3 mg/
kg oral dose. Replacement of one methylene group of
47 with sulfur provided 70 that had no in vivo activity.
The 2-thienyl analogue 71 exhibited potent inhibitory
activity in vitro (IC50 ) 11 nM) and in vivo (ED50 ) 1.1
mg/kg). However, the plasma half-life of 71 in monkey
(T1/2 ) 2.7 h) was much shorter than that of 47 (T1/2
)
6 h). Modification of 64 by oxime insertion led to
analogue 74 with improved in vitro potency but similar
in vivo activity.
Additional derivatives of the bis-QMP ketone 6 were
evaluated including olefin analogues 76-81 and the
oxime 82 (Table 2). These analogues had good in vitro
activity with IC50’s ) 20-50 nM but had disappointing
in vivo activity except for the oxime insertion analogue
79 with 42% inhibition at 3 mg/kg in the rat pleurisy
model.
A series of bis-QMP-spirocyclohexyl analogues 83-
93 was investigated (Table 3). From this limited set, the
oxime insertion analogue 91 exhibited good potency in
both assays.
but both compounds failed to show any activity in vivo
at an oral dose of 3 mg/kg.
A systematic analysis was conducted to identify the
key structural attributes of the bis-QMP series impor-
tant for leukotriene biosynthesis inhibitory activity. The
bis-QMP carboxylates 41 and 45 and the alkyl homo-
logues 42-44 and 46-48 represented the primary
structural units to develop the SAR optimization study.
These carboxylate analogues as the acid or sodium salt
had in vitro inhibitory IC50 values in the range of 23-
After completing this survey of modifications of the
bis-QMP system, the simple pentanoic acid analogue 47

Bis(heteroarylmethoxyphenyl)alkylcarboxylic Acids
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3327
Ta ble 1. SAR of Bis(2-quinolylmethoxyphenyl)alkylcarboxylic Acid Derivatives
in vivo ratb
human neutrophila ED50 (mg/kg) or
compd
R1
R2
IC50 (nM)
%I at 3 mg/kg
mp (oC)
formulac
C35H27N3O5
C36H29N3O5‚H2O*
C38H33N3O5
10
H
ONdCHCO2H
68
21
50
30
37%
1.50
1.00
27%
nt
173
11
12
13
41
H
H
H
H
ONdC(CH3)CO2H
ONdC(CH3)CH2CH2CO2H
ONdC(CH3)CHdCHCO2H
CO2H
94-96
76-78
93-94
C38H31N3O5‚H2O*
60
119-128 C34H26N2O4‚H2O
42
H
H
H
H
CH2CO2H
60
70
17%
30%
50%
43%
53%
25%
46%
0%
94-111
C35H28N2O4‚H2O
42‚Na
43‚Na
44
44‚Na
45
45‚Na
46
47
47‚Na
48
48‚Na
52
53
54
55
56
60
61‚Na
62
CH2CO2-Na+
224-232 C35H27N2O4Na
C(CH3)2CO2-Na+
CH2CH(CH3)CO2H
CH2CH(CH3)CO2-Na+
CO2H
100
82% at 100
46
32
37
170
250-255 C37H31N2O4Na‚0.5H2O
foam
C37H32N2O4‚0.5H2O
C37H31N2O4Na‚0.5H2O
H
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
H
208-210 C35H28N2O4‚H2O
C35H27N2O4Na‚5H2O
94-96
105-106 C37H32N2O4‚0.25H2O
C37H31N2O4Na‚0.25H2O
87-89
CO2-Na+
CH2CO2H
CH2CH2CO2H
C36H30N2O4‚0.75H2O
23
20
43
32
1.50
3.00
32%
35%
7%
CH2CH2CO2-Na+
CH2CH2CH2CO2H
CH2CH2CH2CO2-Na+
CH2CH2CH2OH
C38H34N2O4
C38H33N2O4Na‚0.5H2O
C37H34N2O3‚0.5H2O
C39H35N3O5‚2H2O
C39H35N3O5‚H2O
C39H35N3O5
130
55-58
>125
94-96
80-82
80-82
C(CH3)2CH2ONdCHCO2H
CH2CH2ONdC(CH3)CO2H
CH2CH2CH2ONdCHCO2H
CH2CH2CH2ONdC(CH3)CO2H
CHdNOCH2CO2H
C(CH3)2CHdNOCH2CO2-Na+
CH2CH2CHdNOCH2CO2H
t-CO2H
34
27%
23%
0%
54% at 25
30
35
4%
C40H37N3O5
35
nt
104-108 C36H29N3O5‚1.5H2O
H
28
40
42%
0%
C39H34N3O5Na
C39H35N3O5‚0.5H2O
Me
OH
H
78-80
169-172 C36H26N2O4‚0.5H2O
176-178 33H26N2O3
129-131 C34H28N2O3
65-67 C37H28N2O3S
64
65
98% at 780
170
48%
2%
OH
C
66
CH3
OH
50
0%
67
2-thienyl OH
87% at 100
0%
69
70
H
CH3
SCH2CO2H
SCH2CO2H
58
nt
175-180 C35H28N2O4S‚H2O
62% at 25
0%
92-94
99-101
C36H30N2O4S*
C39H30N2O4S2‚0.75H2O
71
71‚Na
72
2-thienyl SCH2CO2H
11
nt
1.10
80%
nt
2-thienyl SCH2CO2-Na+
>80(dec) C39H29N2O4S2Na‚1.5H2O
Ph
SCH2CO2H
87% at 25
59
89-91
C41H32N2O4S‚0.25H2O
C40H32N3O6Na‚H2O
74‚Na
OH
t-CH2CH2ONdC(CH3)CO2-Na+
40%
a
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophils. The 95% confidence limits were (<20%
b
of the mean value. Ionophore-induced rat pleurisy. The 95% confidence limits were (<50% of the mean value. Dose-response studies
were conducted for the more promising compounds, and ED50 values (mg/kg) are reported as the mean of separate dose determinations.
c All compounds had analyses (0.4% of the theoretical, except as indicated by an asterisk. nt ) not tested.
Ta ble 2. SAR of Bis(2-quinolylmethoxyphenyl) Alkenyl and Oxime Derivatives
human neutrophila
IC50 (nM)
in vivo ratb
%I at 3 mg/kg
compd
X
R
mp (oC)
formulac
76
76‚Na
78
79
81
82
CH
CH
CH
CH
CH
N
CO2H
50
40
11%
19%
17%
42%
10%
0%
128-130
C35H26N2O4‚3H2O
C35H25N2O4Na‚2H2O
C37H29N3O5
C38H31N3O5
C37H29N3O5‚1.5H2O
C35H27N3O5‚0.5H2O
CO2-Na+
>200
CH2ONdCHCO2H
CH2ONdC(CH3)CO2H
CHdNOCH2CO2H
OCH2CO2H
100% at 100
90-93
82
125-127
181-183
20
26
32
a
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophils. The 95% confidence limits were (<20%
of the mean value. Ionophore-induced rat pleurisy. The 95% confidence limits were (<50% of the mean value. c All compounds had
analyses (0.4% of the theoretical, except as indicated by an asterisk.
b
was selected as having the most promising properties
for more detailed analysis. The importance of the
2-quinolyl unit was explored by evaluating the sym-
metrical analogues 94-99 and the asymmetrical ana-
logues 104-106 (Table 4). For the symmetrical series,
where both 2-quinolyl groups were replaced, only the

3328 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
Ta ble 3. SAR of Spirocyclic Derivatives
Kolasa et al.
human neutrophila
in vivo ratb
%I at 3 mg/kg
compd
R
IC50 (nM)
mp (oC)
oil
formulac
C41H38N2O4
83
CO2Et
1900
nt
84
84‚Na
85
90‚Na
91‚Na
93
CO2H
60
47
0%
18%
nt
15%
48%
0%
194-199
C39H34N2O4‚0.75H2O
C39H33N2O4Na‚1.25H2O
C39H36N2O3‚H2O*
CO2-Na+
CH2OH
28% at 100
54% at 100
37
65
61-68
ONdCHCO2-Na+
ONdC(CH3)CO2-Na+
dNOCH2CO2H
C40H34N3O5Na
107-113
109-111
C41H36N3O5Na‚2H2O
C40H35N3O5Na‚0.75H2O
a
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophils. The 95% confidence limits were (<20%
of the mean value. Ionophore-induced rat pleurisy. The 95% confidence limits were (<50% of the mean value. c All compounds had
analyses (<0.4% of the theoretical, except as indicated by an asterisk. nt ) not tested.
b
Ta ble 4. SAR of Heterocyclic Substitution on the Diphenolic Acid Template
human neutrophila
IC50 (nM)
in vivo ratb
%I at 3 mg/kg
compd
R1
R2
mp (oC)
formulac
94‚Na
95
96
96‚Na
97‚Na
98‚Na
99
6-fluoro-2-quinolyl
2-naphthyl
2-benzothiazolyl
2-benzothiazolyl
2-pyridyl
6-fluoro-2-quinolyl
2-naphthyl
2-benzothiazolyl
2-benzothiazolyl
2-pyridyl
40
830
46
50
53% at 390
47% at 100
27% at 3125
59% at 3125
95% at 100
52
93% at 100
nt
80
42%
nt
0%
nt
0%
14%
0%
29%
35%
nt
55%
40%
0%
97-99
90-96
C37H29F2N2O4Na
C
C
39H34O4‚1.25H2O
33H28N2O4S2
185-186
105-108 C33H27N2O4S2Na‚1.5H2O
C
C
C
C
C
C
C
C
C
C
29H27N2O4Na‚0.5H2O
35H29N4O4Na‚H2O
35H34N4O4‚H2O*
35H33N4O4Na‚1.5H2O*
35H30N2O4S‚0.75H2O
35H29N2O4SNa‚H2O
38H33NO4‚0.5H2O
38H32NO4Na‚4.25H2O*
36H33N3O4‚H2O*
36H32N3O4Na‚1.25H2O*
2-quinoxalyl
2-quinoxalyl
1-methyl-2-benzimidazolyl 1-methyl-2-benzimidazolyl
1-methyl-2-benzimidazolyl 1-methyl-2-benzimidazolyl
2-benzothiazolyl
110-112
99‚Na
104
2-quinolyl
2-quinolyl
2-quinolyl
2-quinolyl
68-72
60-72
64-68
82-95
95-97
104‚Na 2-benzothiazolyl
105 2-naphthyl
105‚Na 2-naphthyl
106
1-methyl-2-benzimidazolyl 2-quinolyl
106‚Na 1-methyl-2-benzimidazolyl 2-quinolyl
90
10%
a
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophils. The 95% confidence limits were (<20%
of the mean value. Ionophore-induced rat pleurisy. The 95% confidence limits were (<50% of the mean value. c All compounds had
analyses (<0.4% of the theoretical value, except as indicated by an asterisk. nt ) not tested.
b
6-fluoro-2-quinoline replacement 94‚Na showed good in
vivo activity (42% at 3 mg/kg). The best asymmetric
analogue found was 105 with one 2-quinolyl group
replaced by 2-naphthyl (ED50 ) ∼3 mg/kg). Brief
exploration of substitution of the phenyl rings with
chlorine gave 110 which showed potent in vitro activity
(IC50 ) 25 nM in the human neutrophil assay) and good
in vivo potency (ED50 ) 3 mg/kg in the rat pleurisy
model). A shorter plasma half-life in monkey (T1/2 ) 2
h) compared to that for 47 made this a less attractive
lead compound.
The bis-QMP sodium salt 47‚Na was selected as the
most promising preclinical candidate from this inves-
tigation. This compound was readily synthesized in
three steps from the commercially available diphenolic
acid. The compound demonstrated potent leukotriene
inhibitory activity (IC50 ) 20 nM) in intact human
neutrophils. This inhibition could be decreased 3-fold
by washing the drug-treated neutrophils with 10 vol-
umes of fresh buffer followed by stimulation with
calcium ionophore to induce leukotriene biosynthesis.
The ability to wash out the inhibitory activity suggests
a slowly reversible inhibitory process. In a similar assay
addition of 1% bovine serum albumin (BSA) resulted
in >100-fold decrease in inhibitory activity suggesting
a strong interaction of the drug with BSA. In a calcium
ionophore-stimulated human whole blood assay,17
47‚Na inhibited LTB4 production with an IC50 of 13 000
nM.
The marked reduction in potency for 47‚Na in albu-
min-containing media implies high protein binding.
Protein binding measurements indicated >99% binding
of 47‚Na to proteins in human serum. However, this
property of the compound did not detrimentally affect
the in vivo activity in several animal models in tissues
at several sites including the peritoneal and pleural
cavities as well as in the lung. These results described
as follows provide support that 47‚Na , despite high
protein binding, distributes to the target tissues and
provides effective leukotriene biosynthesis inhibition.
The activity of 47‚Na was examined in a supernatant
preparation from sonicated RBL-2H3 cells with 5-li-
poxygenase (5-LO) activity.15 At concentrations up to
300 000 nM, 47‚Na was inactive in blocking 5-LO

Bis(heteroarylmethoxyphenyl)alkylcarboxylic Acids
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3329
oxidative catalysis of arachidonic acid. It is proposed
that 47‚Na inhibits the FLAP interaction with arachi-
donic acid and 5-LO which is necessary for cellular
leukotriene biosynthesis. Direct proof that 47‚Na binds
to FLAP has not been established.
The selectivity of action of 47‚Na was evaluated in
zymosan-stimulated mouse peritoneal macrophages that
produce both LTC4 and PGE2, an assay that can
measure arachidonic acid metabolism catalyzed by 5-LO
or cyclooxygenase.18 In this assay, 47‚Na showed 9000-
fold selectivity for inhibition of LTC4 (IC50 ) 0.16 nM)
over PGE2 (IC50 ) 1500 nM).
design parameters for a new leukotriene inhibitor drug
candidate: (1) potent leukotriene biosynthesis inhibi-
tion, (2) oral pharmacological activity in relevant animal
models, (3) novel chemical composition without reactive
functionality, and (4) efficient cost-effective synthesis.
The persistent optimization of leukotriene biosynthesis
inhibitors has led us to the discovery of 47‚Na (ABT-
080). This compound has proceeded into phase I human
studies for safety and pharmacokinetic evaluation, and
these results will be reported separately. Further clini-
cal studies with 47‚Na will hopefully clarify fundamen-
tal issues regarding the therapeutic benefit of leuko-
triene biosynthesis inhibition in asthma and related
inflammatory disorders.
Preliminary pharmacokinetic properties of 47‚Na
were examined in rat and monkey by measuring the
plasma concentration following intravenous bolus and
oral dosing. Elimination half-lives of 9 and 5 h were
found for 47‚Na following intravenous dosing in rat and
monkey. An oral dose of 1 mg/kg in rats gave a
maximum plasma concentration of 7300 nM at 40 min
postdosing and bioavailability was 80%. An oral dose
of 1 mg/kg in cynomolgus monkeys gave a maximum
plasma concentration of 3400 nM at 40 min postdosing
and 28% bioavailability. A bile duct cannulation study
in monkey resulted in 40% recovery of the oral dose over
a 6-h collection period with a composition of 93%
glucuronide conjugated metabolites, 4% parent drug,
and 3% other metabolites. These results support the
premise that glucuronidation of the carboxylate function
was the major route of metabolism.
Pharmacological evaluation of 47‚Na was conducted
in several in vivo animal models involving leukotriene
biosynthesis. In a model of passive anaphylaxis in the
peritoneal cavity of rats,15 oral administration of 47‚
Na inhibited both LTB4 (ED50 ) 2.5 mg/kg) and LTE4
(ED50 ) 1.0 mg/kg). The dual inhibition at comparable
levels indicates that the site of intervention occurs prior
to the branching point in the leukotriene biosynthetic
pathway where the 5-LO product LTA4 is converted to
LTB4 or alternatively processed through the peptidyl
leukotriene cascade of LTC4 to LTD4 to LTE4. This is
consistent with blocking the actions of FLAP. The
duration of action was studied in this model, and an
oral dose of 10 mg/kg 47‚Na inhibited the production
of LTE4 by >70% for up to 8 h.
Exp er im en ta l Section
Ch em istr y Gen er a l. Melting points were taken on the
Thomas-Hoover melting apparatus and are uncorrected. 1H
NMR spectra were recorded using a Nicolet QE-300 (300 MHz)
instrument. Mass spectra were obtained with Hewlett-Packard
HP5985 spectrometer. Microanalysis were performed by the
Robertson Microlit Laboratories, Inc., Madison, NJ . Reagents
were obtained from Aldrich and Lancaster chemical compa-
nies.
Rep r esen ta tive P r oced u r es for Sch em e 1. Bis(4-(2-
qu in olylm eth oxy)p h en yl)m eth oxyim in oa cetic Acid (10).
To a solution of 4,4′-dihydroxybenzophenone (5) (4.22 g, 20
mmol) and K2CO3 (16.5 g, 120 mmol) in DMF (75 mL) was
added 2-chloromethylquinoline-HCl (8.56 g, 40 mmol) and the
resulting solution was stirred at 60 °C for 16 h. The reaction
mixture was then poured into ice-water (100 mL). The
resulting solid was filtered, washed with 20% ether-hexane
and dried in vacuo to afford 4-(2-quinolylmethoxy)phenyl
ketone (6) (9.3 g, 94%).
To a solution of 6 (1.25 g, 2.5 mmol) in THF-CH3OH (1:1,
60 mL) at room temperature was added NaBH4 (0.37 g, 10
mmol) and the mixture was refluxed for 3 h. The organics were
removed in vacuo, water (30 mL) was added to the residue
and the pH of the mixture was neutralized with a 10% aqueous
citric acid. The resulting precipitate was collected by filtration,
washed with 20% Et2O-hexane and dried in vacuo to afford
bis(4-(2-quinolylmethoxy)phenyl)methanol (7) (1.1 g, 88%) as
a white solid.
To a mixture of 7 (1.10 g, 2.2 mmol), Ph3P (0.65 g, 2.5 mmol)
and N-hydroxyphthalimide (0.41 g, 2.5 mmol) in THF (60 mL)
was added dropwise a solution of DIAD (0.5 mL, 2.5 mmol) in
THF (15 mL). The mixture was stirred at ambient temperature
for 14 h and concentrated in vacuo, and the residue was
chromatographed (silica gel, 9:1 CH2Cl2-EtOAc) to provide
N-phthaloyl-O-(bis(4-(2-quinolylmethoxy)phenyl)methyl)hy-
droxylamine (8) (1.40 g, 98%).
Eosinophils have been implicated as important proin-
flammatory cells in the pathogenesis of asthma. The
intravenous injection of Sephadex G-200 in Brown
Norway rats results in lung eosinophilia and the forma-
tion of peptidyl leukotrienes in the bronchoaeolar lavage
fluid (BAL).19 In this model, the mean of three dose-
response experiments gave an ED50 of 3.3 mg/kg for
inhibition of leukotrienes and an ED50 of 3.5 mg/kg for
inhibition of eosinophil influx in the BAL for 47‚Na
given orally twice daily for 4 days.
A solution of 8 (1.35 g, 2.1 mmol) and hydrazine hydrate
(1.5 mL, 30 mmol) in EtOH (80 mL) was refluxed for 30 min
and then cooled to room temperature. The reaction mixture
was concentrated in vacuo, 10% aqueous Na2CO3 (50 mL) was
added and the mixture was extracted with CH2Cl2. The extract
was washed with water and brine, dried with MgSO4, filtered
and concentrated in vacuo to provide O-bis(4-(2-quinolyl-
methoxy)phenyl)methylhydroxylamine (9) (1.1 g, 99%).
A mixture of 9 (513 mg, 1.0 mmol), glyoxylic acid hydrate
(180 mg, 2.0 mmol), AcOH (0.06 mL, 1.0 mmol) in CH3OH (40
mL), THF (60 mL) and water (20 mL) was stirred at room
temperature for 16 h. The mixture was concentrated in vacuo
and the precipitated solid was filtered and recrystallized from
In a model of airway constriction induced by antigen
challenge in actively sensitized guinea pigs,20 47‚Na
given orally inhibited bronchoconstriction with an ED50
of 0.4 mg/kg. This result represented the best activity
for any leukotriene inhibitor observed in this model in
our laboratory.
1
EtOAc-hexanes to afford 10 (425 mg, 64%): mp 173 °C; H
NMR (300 MHz, DMSO-d6) δ 5.38 (s, 4 H), 6.30 (s, 1 H), 7.05
(d, J ) 8 Hz, 4 H), 7.28 (d, J ) 8 Hz, 4 H), 7.65 (m, 5 H), 7.79
(m, 2 H), 8.01 (t, J ) 8 Hz, 4 H), 8.41 (d, J ) 8 Hz, 2 H), 13.30
(bs, 1 H); MS (DCI-NH3) m/z 570 (M + H)+. Anal. Calcd for
Con clu sion
The bis-QMP analogue, 4,4-bis(4-(2-quinolylmethoxy)-
C
35H27N3O5: C, 72.66; H, 4.84; N, 7.27. Found: C, 72.75; H,
phenyl)pentanoic acid sodium salt (47‚Na ), met our
4.99; N, 7.06.

3330 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
Kolasa et al.
2-(Bis(4-(2-q u in olylm et h oxy)p h en yl)m et h oxyim in o)-
p r op ion ic Acid (11). A mixture of 9 (513 mg, 1.0 mmol),
methyl pyruvate (0.14 mL, 1.5 mmol) and AcOH (0.06 mL, 1.0
mmol) in CH3OH (40 mL), THF (60 mL) and H2O (20 mL) was
stirred at room temperature for 24 h. The organics were
concentrated in vacuo; the mixture was extracted with CH2-
Cl2, dried with MgSO4 and concentrated in vacuo. The residue
was chromatographed (silica gel, 3:1 hexanes-EtOAc) to afford
2-(bis(4-(2-quinolylmethoxy)phenyl)methoxyimino)propionic acid
methyl ester (410 mg, 68%).
refluxed for 3 h. After cooling to room temperature the mixture
was concentrated in vacuo and dissolved in ether. The organic
layer was washed with saturated aqueous NaHCO3 and brine,
dried with MgSO4 and concentrated in vacuo to provide a thick
oil which was crystallized from Et2O-hexane to give 29 (2.3
g, 85%).
To a solution of 29 (2.3 g, 8.4 mmol) in dry DMF (50 mL)
were added powdered K2CO3 (2.76 g, 20 mmol) and 2-chlo-
romethylquinoline-HCl (3.0 g, 17 mmol). The mixture was
heated at 60 °C for 18 h and then cooled to room temperature,
diluted with water, extracted with EtOAc, washed with water
and brine, dried over MgSO4 and concentrated in vacuo. The
residue was chromatographed (silica gel, CH2Cl2-EtOAc, 9:1)
to provide bis(4-(2-quinolylmethyl)phenyl)alkylcarboxylic acid
methyl ester (37) (3.7 g, 77%).
To a solution of 37 (1.11 g, 0.2 mmol) dissolved in 1,4-
dioxane-MeOH (1:1, 100 mL) was added 1 N NaOH (15 mL)
and the mixture was refluxed for 3 h. The mixture was cooled
to room temperature and concentrated in vacuo; the residue
was diluted with water and acidified to pH 3 with 10% aqueous
citric acid. The solid precipitate was collected, dried in vacuo
and crystallized from EtOAc-hexanes to afford 45 (630 mg,
58%): mp 208-210 °C; 1H NMR (300 MHz, DMSO-d6) δ 1.75
(s, 3 H), 5.33 (s, 4 H), 7.01 (d, J ) 9 Hz, 4 H), 7.12 (d, J ) 9
Hz, 4 H), 7.63 (m, 4 H), 7.78 (m, 2 H), 8.01 (t, J ) 8 Hz, 4 H),
8.42 (d, J ) 8 Hz, 2 H), 12.65 (bs, 1 H); MS (DCI-NH3) m/z
541 (M + H)+. Anal. Calcd for C35H28N2O4‚H2O: C, 75.25; H,
5.41; N, 5.01. Found: C, 74.85; H, 4.89; N, 4.92.
Sca led -Up P r ep a r a tion of 4,4-Bis(4-(2-qu in olylm eth -
oxy)p h en yl)p en ta n oic Acid (47). To a solution of 4,4-bis-
(4-hydroxyphenyl)pentanoic acid (143 g, 0.5 mol) in methanol
(800 mL) was added concentrated H2SO4 (4 mL) and the
mixture was heated for 3 h. After cooling to room temperature
the mixture was concentrated in vacuo and the residue was
dissolved in Et2O. The ether solution was washed with
saturated NaHCO3 and brine, dried with anhydrous MgSO4
and concentrated in vacuo. The residue was crystallized from
Et2O-hexane to provide the ester 31 (146 g, 97%): mp 129-
130 °C.
To a solution of the ester in CH3OH (75 mL) was added 1 N
NaOH (5 mL); the mixture was stirred at room temperature
for 16 h and concentrated in vacuo and water (25 mL) was
added to the residue. The solution was washed with Et2O and
then acidified with 50% aqueous citric acid. The precipitated
solid was collected by filtration, dried in vacuo and recrystal-
lized from EtOAc-hexanes to provide 11 as a mixture of E
and Z isomers (4:1, 245 mg, 61%): mp 94-96 °C; 1H NMR
(300 MHz, DMSO-d6) δ 2.03 (s, 3 H), 5.35 (s, 4 H), 6.27 (s, 1
H), 7.04 (d, J ) 8 Hz, 4 H), 7.25 (d, J ) 8 Hz, 4H), 7.63 (m, 4
H), 7.78 (t, J ) 8 Hz, 2 H), 8.02 (t, J ) 8 Hz, 4 H), 8.41 (d, J
) 9 Hz, 2 H); MS (FAB+) m/z 584 (M + H)+. Anal. Calcd for
C
36H29N3O5‚H2O: C, 71.94; H, 5.16; N, 6.99. Found: C, 72.44;
H, 5.15; N, 6.78.
Rep r esen ta tive P r oced u r es for Sch em e 2. (1,5-Bis(4-
(2-qu in olylm eth oxy)ph en yl)-3-pen tyloxy)im in oacetic Acid
(18). To a solution of bis(4-methoxybenzylidene)acetone (14)
(3.5 g, 12 mmol) in THF-MeOH (1:1) (100 mL) was added PtO2
(90 mg) and the resulting mixture was stirred at room
temperature under 4 atm of H2 for 19 h. The catalyst was
filtered and washed with THF, and the filtrate was concen-
trated in vacuo. The residue was chromatographed (silica gel,
3:1 hexanes-EtOAc) to afford 1,5-bis(4-methoxyphenyl)-3-
pentanone (2.13 g, 60%) and 1,5-bis(4-methoxyphenyl)-3-
pentanol (1.0 g) as a byproduct.
A mixture of the pentanone (2.1 g, 7 mmol) and AlBr3 (10.64
o
g, 40 mmol) in toluene (60 mL) was refluxed at 80 C for 30
min and then cooled to room temperature. The reaction
mixture was slowly added to a mixture of 1 N HCl (150 mL)
and Et2O (150 mL). The ether layer was separated, washed
with 1 N HCl, water, and brine and dried over anhydrous
MgSO4 to provide crude solid 1,5-bis(4-hydroxyphenyl)-3-
pentanone (15) (2.0 g). A mixture of crude 15 (2.0 g, ∼7 mmol),
2-chloromethylquinoline-HCl (3.55 g, 20 mmol) and anhydrous
K2CO3 (2.76 g, 20 mmol) in DMF (40 mL) was stirred at
ambient temperature for 36 h and then poured into water. The
crude solid 16 (∼ 5 g) was filtered and used directly in the
next step. A solution of crude 16 (2,21 g, 4 mmol) and NaBH4
(152 mg, 4 mmol) in dioxane (15 mL) and EtOH (35 mL) was
refluxed for 30 min. The pH of reaction mixture was adjusted
to 5, water was added, and the precipitated solid was filtered
and dried in vacuo to afford alcohol 17 (2.3 g, 41%).
To a solution of the ester 31 (60 g, 0.2 mol) in DMF (300
mL) was added Cs2CO3 (137 g, 0.4 mol), the mixture was
stirred for 20 min at ambient temperature after which 2-chlo-
romethylquinoline (74 g, 0.42 mol) was added, and the mixture
was stirred for 14 h at room temperature. Water (1000 mL)
was added and the product was extracted with EtOAc. The
acetate layer was washed with water and brine, dried with
MgSO4 and concentrated in vacuo to provide 39 (113 g, 97%)
as an orange-colored oil.
To a solution of 39 (226 g, 0.38 mol) in dioxane-MeOH
(1:1, 1400 mL) was added 2.5 N NaOH (225 mL) and the
reaction mixture was stirred at ambient temperature for 5 h.
The mixture was concentrated in vacuo; the residue was
diluted with water (500 mL) and acidified with 10% aqueous
citric acid to pH 4. The precipitated solid was collected by
filtration, washed with water and dried in vacuo. Crystalliza-
tion from EtOAc provided the first crop of 47 (157 g, 73%) (the
mother liquor still contained large amounts of product): mp
According to the method used for 10, the alcohol 17 was
converted in three steps to 18 (45%): 1H NMR (300 MHz,
DMSO-d6) δ 1.85 (m, 4 H), 2.55 (m, 4 H), 4.16 (m, 1 H), 5.33
(s, 4 H), 6.94 (d, J ) 9 Hz, 4 H), 7.10 (d, J ) 9 Hz, 4 H), 7.62
(m + s, 5 H), 7.78 (m, 2 H), 8.00 (m, 4 H), 8.40 (d, J ) 8 Hz,
2 H); MS (DCI-NH3) m/z 626 (M + H)+. Anal. Calcd for
1
105-106 °C; H NMR (300 MHz, DMSO-d6) δ 1.50 (s, 3 H),
C
39H35N3O5‚H2O: C, 72.77; H, 5.79; N, 6.53. Found: C, 73.21;
1.95 (m, 2 H), 2.27 (m, 2 H), 5.34 (s, 4 H), 6.98 (d, J ) 8 Hz,
4 H), 7.10 (d, J ) 8 Hz, 4 H), 7.65 (m, 4 H), 7.80 (m, 2 H), 8.00
(m, 4 H), 8.42 (d, J ) 9 Hz, 2 H), 12.00 (s, 1H); MS (DCI-
NH3) m/z 569 (M + H)+. Anal. Calcd for C37H32N2O4‚0.25
H2O: C, 77.53; H, 5.71; N, 4.88. Found: C, 77.52; H, 5.88; N,
4.60.
H, 5.71; N, 6.41.
Rep r esen ta tive P r oced u r es for Sch em e 3. 2,2-Bis(4-
(2-qu in olylm eth oxy)p h en yl)p r op ion ic Acid (45). To a
stirred ice-cooled mixture of phenol (9.4 g, 0.1 mol), pyruvic
acid (4.4 g, 0.05 mol) and water was added dropwise concen-
trated H2SO4 (4.5 mL, 18.0 g). After 15 min the ice bath was
removed, and the reaction mixture was warmed to room
temperature and stirred for 18 h. The mixture was diluted with
Et2O-H2O (200 mL, 1:1) and the organic layer was extracted
with 20% aqueous NaHCO3. This extract was acidified,
extracted with Et2O, dried with MgSO4 and concentrated in
vacuo to provide 2,2-bis(4-hydroxyphenyl)propionic acid (22)
(6.2 g, 48%).
4,4-Bis(4-(2-qu in olylm eth oxy)p h en yl)p en ta n oic Acid
Sod iu m Sa lt (47‚Na ). Compound 47 (150 g, 0.26 mol) was
suspended in THF-EtOH (1:1, 1400 mL) and powdered NaOH
(10.2 g, 0.26 mol) was added. The mixture was stirred at room
temperature for 30 min until the solution became clear. The
mixture was concentrated in vacuo, the residue was triturated
with Et2O (1500 mL), and the solid was collected by filtration,
ground by mortar and pestle and dried under vacuum to
provide 47‚Na (152 g, 98%): 1H NMR (300 MHz, DMSO-d6) δ
1.47 (s, 3 H), 1.63 (m, 2 H), 2.18 (m, 2 H), 5.31 (s, 4 H), 6.95
To a solution of 22 (2.58 g, 10 mmol) in MeOH (40 mL) was
added concentrated H2SO4 (0.3 mL) and the mixture was

Bis(heteroarylmethoxyphenyl)alkylcarboxylic Acids
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3331
(d, J ) 9 Hz, 4 H), 7.08 (d, J ) 9 Hz, 4 H), 7.64 (m, 4 H), 7.78
(m, 2 H), 8.00 (m, 4 H), 8.40 (d, J ) 8 Hz, 2 H); MS (FAB+)
m/z 591 (M + H)+, (FAB-) 589 (M - H)-. Anal. Calcd for
product was extracted with EtOAc and the extracts were
concentrated in vacuo and purified by chromatography (silica
gel, 4:1 CH2Cl2-EtOAc) to afford 4,4-bis(4-(2-quinolylmeth-
oxy)phenyl)-4-hydroxy-2-butynoic acid methyl ester (63) (730
mg, 63%).
C
37H31N2O4Na‚0.25H2O: C, 74.67; H, 5.34; N, 4.71. Found: C,
74.57; H, 5.32; N, 4.52..
A mixture of 1 N NaOH (2 mL) and 63 (730 mg, 0.12 mmol)
in dioxane (25 mL) and methanol (10 mL) was stirred at
ambient temperature for 10 h. The mixture was concentrated
in vacuo, the residue was diluted with water and acidified to
pH 3 with 1 N HCl. The solids were collected by filtration,
washed with water, dried in vacuo and triturated with Et2O-
EtOAc (8:1) to provide 64 (380 mg, 56%): mp 169-172 °C; 1H
NMR (300 MHz, DMSO-d6) δ 5.35 (s, 4 H), 7.04 (d, J ) 9 Hz,
4 H), 7.37 (d, J ) 9 Hz, 4 H), 7.63 (m, 4 H), 7.78 (m, 2 H), 8.00
(m, 4 H), 8.40 (d, J ) 8 Hz, 2 H), 13.75 (bs, 1 H); MS (DCI-
NH3) m/z 567 (M + H)+. Anal. Calcd for C36H26N2O4‚0.5 H2O:
C, 75.12; H, 4.73; N, 4.89. Found: C, 75.19; H, 4.80; N, 4.60.
Bis(4-(2-qu in olylm eth oxy)p h en yl)m eth a n ol (65). To a
solution of 6 (640 mg, 1.3 mmol) in THF-MeOH (1:1, 30 mL)
was added NaBH4 (190 mg, 5.2 mmol) and the mixture was
refluxed for 3 h. The mixture was concentrated in vacuo, the
residue was diluted with water and acidified with 10% citric
acid and the precipitated product was collected by filtration,
washed with water and dried in vacuo. Recrystallization from
Et2O-hexanes provided 65 (580 mg, 90%): mp 176-178 °C;
1H NMR (300 MHz, DMSO-d6) δ 5.32 (s, 4 H), 5.58 (s, 1 H),
5.67 (broad s, 1 H), 6.96 (d, J ) 9 Hz, 4 H), 7.24 (d, J ) 9 Hz,
4 H), 7.61 (m, 4 H), 7.78 (m, 2 H), 7.98 (t, J ) 9 Hz, 4 H), 8.39
(d, J ) 9 Hz, 2 H); MS (DCI-NH3) m/z 499 (M + H)+.
Rep r esen ta tive P r oced u r es for Sch em e 4. 4,4-Bis(4-
(2-qu in olylm eth oxy)p h en yl)p en ta n ol (52). To a mixture
of 39 (1.75 g, 3 mmol) and NaBH4 (380 mg, 10 mmol) in THF
o
(50 mL) was added dropwise methanol at 50-55 C and the
mixture stirred for the next 30 min. The mixture was then
cooled to room temperature, poured into water (50 mL) and
acidified to pH 4. The resulting mixture was extracted with
EtOAc, dried with MgSO4 and concentrated in vacuo. The
residue was chromatographed (silica gel, 3:1 CH2Cl2-EtOAc)
to afford 52 (1.46 g, 88%): mp 55-58 °C; 1H NMR (300 MHz,
DMSO-d6) δ 1.18 (m, 2 H), 1.48 (s, 3 H), 2.00 (m, 2 H), 3.34
(m, 2 H), 4.34 (t, J ) 6 Hz, 1 H), 5.30 (s, 4 H), 6.96 (d, J ) 9
Hz, 4 H), 7.09 (d, J ) 9 Hz, 4 H), 7.64 (m, 4 H), 7.79 (m, 2 H),
8.00 (t, J ) 8 Hz, 4 H), 8.41 (d, J ) 8 Hz. 2 H); MS (DCI-
NH3) m/z 555 (M + H)+. Anal. Calcd for C37H34N2O3‚0.5H2O:
C, 78.84; H, 6.44; N, 4.97. Found: C, 78.67; H, 5.95; N, 4.70.
4,4-Bis(4-(2-qu in olylm eth oxy)ph en yl)-1-pen tyloxyim in o-
2-p r op ion ic Acid (56). According to the procedure for 11,
compound 52 was converted to 56 (0.26 g, 75%): mp 80-82
1
°C; H NMR (300 MHz, DMSO-d6) δ 1.42 (m, 2 H), 1.53 (s, 3
H), 1.90 (s, 3 H), 2.05 (m, 2 H), 4.11 (t, J ) 7 Hz, 2 H), 5.33 (s,
4 H), 6.95 (d, J ) 9 Hz, 4 H), 7.09 (d, J ) 9 Hz, 4 H), 7.64 (m,
4 H), 7.78 (m, 2 H), 8.00 (m, 4 H), 8.41 (d, J ) 8 Hz, 2 H); MS
(DCI-NH3) m/z 640 (M + H)+. Anal. Calcd for C40H37N3O5:
C, 75.10; H, 5.83; N, 6.57. Found: C, 74.86; H, 6.11; N, 6.27.
1,1-Bis(4-(2-qu in olylm eth oxy)p h en yl)eth a n ol (66). To
a solution of 6 (992 mg, 2 mmol) in THF (20 mL) at -78 oC
was added methylmagnesium bromide (3 M solution in Et2O,
0.8 mL, 2.4 mmol) and the resulting mixture was stirred at
room temperature for 12 h. The mixture was quenched with
saturated NH4Cl and extracted with ethyl acetate. The extract
was washed with water and brine, dried with MgSO4 and
concentrated in vacuo. The residue was chromatographed
(silica gel, 4:1 CH2Cl2-EtOAc) to afford 66 (920 mg, 90%): mp
3,3-Bis(4-(2-qu in olylm eth oxy)p h en yl)-2,2-d im eth yl-1-
p r op ylid en ea m in ooxya cetic Acid Sod iu m Sa lt (61‚Na ).
To a stirred THF (50 mL) solution of 35 (1.33 g, 2.28 mmol) at
room temperature was added LiAlH4 (0.09 g, 2.5 mmol) and
the mixture was stirred 3 h. Water (0.1 mL) was added
followed by the addition of 1 N NaOH (0.1 mL) and water (0.5
mL). The mixture was then concentrated to dryness and
partitioned between water and ethyl acetate. The organic layer
was washed with brine, dried over MgSO4, concentrated in
vacuo and purified by column chromatography (silica gel, 3:2
EtOAc-hexanes) to afford 50 (1.01 g, 80%).
To a solution of 50 (0.4 g, 0.72 mmol) in dry CH2Cl2 (15 mL)
was added DMSO (0.17 g, 2.17 mmol). The mixture was cooled
to -78 °C and oxalyl chloride (0.14 g, 1.08 mmol) was added.
The mixture was stirred for 0.5 h, triethylamine (0.37 g, 3.6
mmol) was added and the mixture was allowed to warm to
room temperature. The mixture was concentrated in vacuo and
triturated with dry THF. The THF solution was filtered and
the solids were washed with additional THF. The combined
THF solution was concentrated in vacuo to give crude 58 which
was immediately reacted with a mixture of carboxylmethy-
oxyamine hemi-HCl (110 mg, 1 mmol) and AcONa‚3H2O (138
mg, 1 mmol) in 1,4-dioxane (10 mL), MeOH (7 mL) and H2O
(5 mL) at room temperature for 8 h. The mixture was then
concentrated in vacuo, water (10 mL) was added and the
product was filtered, washed with water and dried in vacuo
to provide 61 (315 mg, 77%). According to the procedure for
42‚Na , compound 61 was converted to the sodium salt 61‚
Na : 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 6 H), 3.89 (s, 1
H), 4.06 (s, 2 H), 5.32 (s, 4 H), 6.97 (d, J ) 9 Hz, 4 H), 7.31 (d,
J ) 9 Hz, 4 H), 7.46 (s, 1 H), 7.65 (m, 4 H), 7.78 (m, 2 H), 8.01
(t, J ) 9 Hz, 4 H), 8.40 (d, J ) 9 Hz, 2 H); MS (FAB+) m/z 648
(M + Na)+, 626 (M + H)+.
1
129-131 °C; H NMR (300 MHz, DMSO-d6) δ 1.74 (s, 3 H),
5.32 (s, 4 H), 5.48 (s, 1 H), 6.95 (d, J ) 9 Hz, 4 H), 7.30 (d, J
) 9 Hz, 4 H), 7.63 (m, 4 H), 7.78 (m, 2 H), 8.01 (m, 4 H), 8.39
(d, J ) 8 Hz, 2 H); MS (DCI-NH3) m/z 513 (M + H)+. Anal.
Calcd for C34H28N2O3: C, 79.67; H, 5.51; N, 5.46. Found: C,
79.48; H, 5.62; N, 5.25.
Bis(4-(2-qu in olylm eth oxy)ph en yl)m eth ylth ioacetic Acid
(69). To a solution of 65 (0.75 g, 1.51 mmol) in CH2Cl2-CHCl3
(1:1, 8 mL) was added ZnI2 (0.601 g, 1.91 mmol). After stirring
10 min, ethyl 2-mercaptoacetate (0.239 mL, 2.18 mmol) was
added and the mixture was stirred for 14 h at room temper-
ature. Water was added and product was extracted with
CHCl3. The organic layer was washed with water and brine,
dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by chromatography (silica gel, 2:1 hex-
anes-EtOAc) to provide the ethyl ester intermediate (650 mg,
72%).
The ester (0.609 g, 1.01 mmol) was dissolved in a mixture
of EtOH-THF (3:1, 20 mL) at room temperature and 1 N
NaOH (1.27 mL, 1.27 mmol) was added. The reaction mixture
was refluxed for 15 h, H2O (50 mL) was added, followed by
10% aqueous citric acid to pH 3, and the product was extracted
with EtOAc. The organic layer was washed with water and
brine, dried over MgSO4 and concentrated in vacuo. The
residue was triturated with hexane and the solid was collected
by filtration to provide 69 (300 mg, 52%): mp 175-180 °C; 1H
NMR (300 MHz, DMSO-d6) δ 3.02 (s, 2 H), 5.29 (s, 1 H), 5.34
(s, 4 H), 7.03 (d, J ) 9 Hz, 4 H), 7.33 (d, J ) 9 Hz, 4 H), 7.63
(m, 4 H), 7.79 (m, 2 H), 8.00 (m, 4 H), 8.41 (d, J ) 9 Hz, 1 H),
12.51 (br s, 1 H); MS (DCI-NH3) m/z 573 (M + H)+. Anal.
Rep r esen ta tive P r oced u r es for Sch em e 5. 4,4-Bis(4-
(2-qu in olylm eth oxy)p h en yl)-4-h yd r oxy-2-bu tyn oic Acid
(64). To a solution of 6 (980 mg, 2 mmol) and propiolic acid
(0.19 mL, 3 mmol) in THF (40 mL) at -78 °C was added LDA
(1.5 M solution in THF, 4 mL, 6 mmol) and the mixture was
left at room temperature for 24 h. Water was added; the
mixture was acidified to pH 5 and extracted with ethyl acetate.
The extract was dried with MgSO4 and concentrated in vacuo.
The residue was dissolved in DMF (40 mL) and treated with
methyl iodide (2 mL) and NaHCO3 (170 mg, 2 mmol) for 24 h
at room temperature. The mixture was poured into water, the
Calcd for
Found: C, 71.08; H, 5.11; N, 4.41.
C35H28N2O4S‚H2O: C, 70.95; H, 5.14; N, 4.73.
1,1-Bis(4-(2-qu in olylm eth oxy)p h en yl)-1-eth ylth ioa ce-
tic Acid (70). A mixture of 66 (300 mg, 0.6 mmol) and ethyl
2-mercaptoacetate (0.1 mL, 0.7 mmol) in CH2Cl2 (15 mL) at 0
°C was treated with BF3‚Et2O (0.24 mL, 2 mmol) and the

3332 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
Kolasa et al.
mixture was left at 0 °C for additional 1 h. The mixture was
then quenched with saturated NH4Cl and extracted with CH2-
Cl2. The extract was dried with MgSO4 and concentrated in
vacuo. The residue was chromatographed (silica gel, 9:1 CH2-
Cl2-EtOAc) to provide the ethyl ester intermediate (220 mg,
60%).
According to the procedure for 69, the ester was hydrolyzed
to afford 70 (170 mg, 80%): mp 92-94 °C; 1H NMR (300 MHz,
DMSO-d6) δ 2.00 (s, 3 H), 3.32 (s, 2 H), 5.34 (s, 4 H), 7.02 (d,
J ) 9 Hz, 4 H), 7.30 (d, J ) 9 Hz, 4 H), 7.63 (m, 4 H), 7.78 (m,
2 H), 8.00 (m, 4 H), 8.41 (d, J ) 8 Hz, 2 H); MS (DCI-NH3)
m/z 587 (M + H)+. Anal. Calcd for C36H30N2O4S: C, 73.70; H,
5.15; N, 4.77. Found: C, 74.24; H, 5.28; N, 4.34.
mmol). The mixture was stirred 1 h, quenched with aqueous
saturated NH4Cl, and extracted with Et2O (100 mL). The
extract was washed with brine, dried with MgSO4, filtered,
and concentrated in vacuo and the residue was chromato-
graphed (silica gel, 1:12 CH3OH-CH2Cl2) to provide 3,3-bis-
(4-(2-quinolylmethoxy)phenyl)-2-propen-1-ol (77) (530 mg, 50%)
as a yellow oil.
According to the procedure for 10, compound 77 was
1
converted to 78 (280 mg, 47%): mp 90-93 °C; H NMR (300
MHz, DMSO-d6) δ 4.67 (d, J ) 8 Hz, 2 H), 5.38 (s, 2 H), 5.41
(s, 2 H), 6.13 (t, J ) 8 Hz, 1 H), 7.08 (m, 8 H), 7.72 (m, 7 H),
8.42 (t, J ) 9 Hz, 2 H); MS (DCI-NH3) m/z 596 (M + H)+.
3,3-Bis(4-(2-qu in olylm et h oxy)p h en yl)p r op en -1-ylid e-
n ea m in ooxya cetic Acid (81). A mixture of 77 (0.52 g, 1
mmol) and BaMnO4 (2.56 g, 10 mmol) in toluene (30 mL) was
refluxed for 3 h. The mixture was filtered through a pad of
Celite, and the filtrate was concentrated under reduced
pressure to provide 0.51 g of crude 3,3-bis(4-(2-quinolyl-
methoxy)phenyl)-2-propenal which was used without further
purification. According to the procedure for 61, this aldehyde
(0.51 g, 1 mmol) was converted to acid 81 (0.12 g, 19%) as a
5,5-Bis(4-(2-q u in olylm e t h oxy)p h e n yl)-5-h yd r oxy-3-
p en tyn -1-yloxyim in o-2-p r op ion ic Acid Sod iu m Sa lt (74‚
Na ). To a solution of 6 (496 mg, 1 mmol) in THF (25 mL) at
o
-50 C was added a solution of the dilithium salt of 3-butyn-
1-ol, prepared by addition of 1.5 M LDA (3 mL) to 3-butyn-1-
o
ol (0.15 mL, 2 mmol) at -50 C and the reaction mixture was
allowed to warm to room temperature. The mixture was stirred
for 12 h and then quenched with saturated NH4Cl. The product
was extracted with EtOAc and purified by chromatography
(silica gel, EtOAc) to provide 5,5-bis(4-(2-quinolylmethoxy)-
phenyl)-5-hydroxy-3-butyn-1-ol (73) (400 mg, 88%).
1
white powder: mp 125-127 °C; H NMR (300 MHz, DMSO-
d6) δ 4.51 (s, 2 H), 5.40(s, 2 H), 5.45 (s, 2 H), 6.68 (d, J ) 9 Hz,
1 H), 7.15 (m, 6 H), 7.70 (m, 7 H), 8.02 (m, 4 H), 8.45 (t, J )
9 Hz, 2 H), 12.75 (broad s, 1 H); MS (DCI-NH3) m/z 596 (M +
H)+. Anal. Calcd for C37H29N3O5‚1.5H2O: C, 71.31; H, 5.14;
N, 6.75. Found: C, 71.61; H, 5.04; N, 6.67.
According to the procedure for 11, the alcohol 73 was
converted to the acid 74 (130 mg, 20%) which was converted
to the corresponding sodium salt by the procedure described
for 42‚Na : mp 108-111 °C; 1H NMR (300 MHz, DMSO-d6) δ
1.83 (s, 3 H), 2.61 (t, J ) 7 Hz, 2 H), 4.10 (t, J ) 7 Hz, 2 H),
5.32 (s, 4 H), 6.96 (d, J ) 9 Hz, 4 H), 7.40 (d, J ) 9 Hz, 4 H),
7.62 (m, 4 H), 7.78 (m, 2 H), 8.00 (m, 4 H), 8.40 (d, J ) 8 Hz,
2 H); MS (FAB+) m/z 674 (M + Na)+, 652 (M + H)+, (FAB-)
m/z 651 (M - H)-. Anal. Calcd for C40H32N3O6Na‚H2O: C,
69.46; H, 4.95; N, 6.07. Found: C, 69.62; H, 5.10; N, 5.61.
Rep r esen ta tive P r oced u r es for Sch em e 6. 3,3-Bis(4-
(2-qu in olylm eth oxy)p h en yl)p r op en oic Acid (76). A solu-
tion of diisopropylamine (0.40 g, 4 mmol) in dry THF (25 mL)
was cooled to -78 °C and treated with n-BuLi (1.6 mL, 4
mmol). The mixture was stirred for 15 min and then ethyl
trimethysilylacetate (0.64 g, 4 mmol) was added. The solution
was stirred 15 min and a solution of 6 (1.0 g, 2 mmol) in THF
(20 mL) was added. The reaction was stirred for 30 min and
then allowed to warm to room temperature, after which
KHSO4 (0.75 g) was added followed by water (50 mL). The
mixture was extracted with Et2O; the extract was washed with
water and brine, dried with MgSO4 and concentrated in vacuo.
The residue was purified by chromatography (silica gel, 9:1
CH2Cl2-EtOAc) to provide 75 (0.92 g, 82%) as a white solid.
To a solution of 75 (0.56 g, 1 mmol) in 1,4-dioxane-EtOH
(1:1, 30 mL) was added 1 N NaOH (8 mL) and the reaction
mixture was refluxed for 3 h. The mixture was cooled to room
temperature, water was added, the mixture was concentrated
in vacuo and acidified with 10% citric acid to pH 3 and the
precipitated solid was collected by filtration, washed with
water and recrystallized from 95% ethanol to provide 76 (0.47
g, 87%): mp 128-130 °C; 1H NMR (300 MHz, DMSO-d6) δ
5.40 (s, 4 H), 6.20 (s, 1 H), 7.08 (m, 6 H), 7.21 (d, J ) 9 Hz, 2
H), 7.73 (m, 6 H), 8.03 (m, 4 H), 8.44 (t, J ) 9 Hz, 2 H), 11.97
(broad s, 1 H); MS (DCI-NH3) m/z 538 (M + H)+. Anal. Calcd
for C35H26N2O4‚3H2O: C, 70.95; H, 5.41; N, 4.73. Found: C,
70.53; H, 5.24; N, 4.61.
Bis(4-(2-qu in olylm eth oxy)p h en yl)m eth ylid en ea m in o-
oxya cet ic Acid (82). According to the procedure for 61,
compound 6 (1.25 g, 2.5 mmol) and carboxylmethoxyamine
hemi-HCl (0.56 g, 2.5 mmol) were converted to 82 (0.26 g,
18%): mp 181-183 °C; 1H NMR (300 MHz, DMSO-d6) δ 4.61
(s, 2 H), 5.39 (s, 2 H), 5.42 (s, 2 H), 7.08 (d, J ) 9 Hz, 2 H),
7.16 (d, J ) 9 Hz, 2 H), 7.31 (d, J ) 9 Hz, 2 H), 7.38 (d, J ) 9
Hz, 2 H), 7.67 (m, 4 H), 7.80 (m, 2 H), 8.01 (m, 4 H), 8.43 (t, J
) 8 Hz, 2 H), 12.75 (broad s, 1 H); MS (DCI-NH3) m/z 570 (M
+ H)+. Anal. Calcd for C35H27N3O5‚0.5H2O: C, 72.70; H, 4.88;
N, 7.27. Found: C, 72.47; H, 4.67; N, 7.07.
Rep r esen ta tive P r oced u r es for Sch em e 7. 4,4-Bis(4-
(2-q u in olylm et h oxy)p h en yl)cycloh ex-1-yloxyim in oa ce-
t ic Acid Sod iu m Sa lt (90‚Na ). To a solution of 1,4-
cyclohexanedione monoethylene ketal (86) (3.12 g, 20 mmol)
in 1,4-dioxane (25 mL) and EtOH (45 mL) was added NaBH4
(0.38 g, 10 mmol) and the resulting mixture was refluxed for
45 min. The mixture was then cooled to room temperature,
acidified to pH 5 with 10% citric acid and extracted with EtOAc
to afford 1-hydroxy-4-cyclohexanone ethylene ketal (87) (2.8
g).
A mixture of 87 (2.8 g, 17.7 mmol) and phenol (5.64 g, 60
o
mmol) in 1,4-dioxane (10 mL) and water (10 mL) at 0 C was
treated dropwise with concentrated H2SO4 (20 mL). The
mixture was allowed to warm to room temperature and stirred
for 6 h. The reaction mixture was poured into ice-water and
extracted with EtOAc. The acetate layer was washed with
water and brine, dried with MgSO4 and concentrated in vacuo
to provide 4,4-bis(4-hydroxyphenyl)-1-cyclohexanol (88) (5 g)
contaminated with phenol.
A solution of 88 in DMF (100 mL) was treated with K2CO3
(11.04 g, 80 mmol) and 2-chloromethylquinoline-HCl (12.84
g, 60 mmol) for 20 h at ambient temperature. The mixture
was diluted with water (500 mL) and extracted with EtOAc.
The organic layer was washed with water and brine, dried with
MgSO4 and concentrated in vacuo. The residue was purified
by chromatography (silica gel, 4:1 CH2Cl2-EtOAc) to provide
4,4-bis(4-(2-quinolylmethoxy)phenyl)-1-cyclohexanol (89) (5.25
g, 52%).
According to the procedure for 10, compound 89 was
converted to the acid 90 (75%) and subsequently to its sodium
salt 90‚Na by the procedure for 42‚Na : 1H NMR (300 MHz,
DMSO-d6) δ 1.45 (m, 2 H), 1.76 (m, 2 H), 2.02 (m, 2 H), 2.45
(m, 2 H), 4.04 (m, 1 H), 5.30 (two s, 4 H), 6.91 (d, J ) 9 Hz, 2
H), 6.98 (d, J ) 9 Hz, 2 H), 7.20 (d, J ) 9 Hz, 2 H), 7.27 (d, J
) 9 Hz, 2 H), 7.62 (m, 4 H), 7.78 (m, 2 H), 8.00 (m, 4 H), 8.40
(two d, J ) 8 Hz, 2 H); MS (FAB+) m/z 638 (M + H)+, 660 (M
3,3-Bis(4-(2-qu in olylm eth oxy)p h en yl)p r op en oic Acid
Sod iu m Sa lt (76‚Na ). According to the procedure for 42‚Na ,
the acid 76 (0.43 g, 0.8 mmol) was converted into its sodium
salt 76‚Na (340 mg): mp > 200 °C; 1H NMR (300 MHz,
DMSO-d6) δ 5.34 (s, 4 H), 6.03 (s, 1 H), 6.97 (m, 4 H), 7.07 (d,
J ) 9 Hz, 2 H), 7.18 (d, J ) 9 Hz, 2 H), 7.65 (m, 4 H), 7.80 (m,
2 H), 8.01 (m, 2 H), 8.42 (m, 2 H); MS (FAB+) m/z 561 (M +
Na)+. Anal. Calcd for C35H25N2O4Na‚2H2O: C, 70.37; H, 4.85;
N, 4.69. Found: C, 70.73; H, 4.59; N, 4.54.
3,3-Bis-(4-(2-q u in olylm et h oxy)p h en yl)-2-p r op en yl-1-
oxyim in oa cetic Acid (78). To a solution of 75 (1.1 g, 2 mmol)
in dry THF (25 mL) cooled to -23 °C with a CCl4-dry ice bath
was added slowly a solution of 1 N LiEt3BH in THF (4 mL, 4

Bis(heteroarylmethoxyphenyl)alkylcarboxylic Acids
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3333
+ Na)+, (FAB-) m/z 636 (M - H)-. Anal. Calcd for C40H34N3O5-
Na: C, 72.82; H, 5.19; N, 6.36. Found: C, 72.51; H, 5.35; N,
6.71.
1H), 7.79 (m, 1 H), 8.00 (m, 3 H), 8.12 (d, J ) 9 Hz, 1 H), 8.42
(d, J ) 9 Hz, 1 H), 12.05 (br s, 1 H); MS (DCI-NH3) m/z 575
(M + H)+. Anal. Calcd for C35H30N2O4‚0.75H2O: C, 71.46; H,
5.39; N, 4.76. Found: C, 71.38; H, 5.05; N, 4.73.
4,4-Bis(4-(2-qu in olylm eth oxy)p h en yl)-1-cycloh exylid e-
n ea m in ooxya cetic Acid (93). To a mixture of 89 (1.13 g, 2
mmol) and molecular sieves (3 g) in CH2Cl2 (40 mL) was added
pyridinium chlorochromate (PCC; 0.65 g, 3 mmol) and the
resulting mixture was stirred at room temperature for 30 min.
The mixture was filtered through a pad of Celite, the filtrate
was concentrated in vacuo to 10 mL and then chromato-
graphed (silica gel, 4:1 CH2Cl2-EtOAc) to afford 4,4-bis(4-(2-
quinolylmethoxy)phenyl)-1-cyclohexanone (92) (0.25 g, 23%).
A mixture of 92 (0.25 g, 0.44 mmol), H2NOH‚HCl (0.035 g,
0.5 mmol) and AcONa‚3H2O (0.68 g, 0.5 mmol) in 1,4-dioxane
(15 mL), MeOH (10 mL) and H2O (8 mL) was stirred at room
temperature for 18 h and then concentrated in vacuo. Water
was added to the residue; the solid was collected by filtration
and dried in vacuo to provide 4,4-bis(4-(2-quinolylmethoxy)-
phenyl)-1-cyclohexanone oxime (0.22 g, 86%).
A solution of oxime (0.22 g, 0.38 mmol) in DMF (20 mL)
was treated with ethyl bromoacetate (0.06 mL, 0.5 mmol) in
the presence of Cs2CO3 (0.17 g, 0.5 mmol) for 48 h at room
temperature. The mixture was then diluted with water and
extracted with EtOAc. The acetate layer was washed with
water and brine, dried with MgSO4 and concentrated in vacuo.
The residue was chromatographed (silica gel, 2:1 CH2Cl2-
EtOAc) to provide the ethyl ester intermediate (0.125 g) which
was hydrolyzed by treating with 1 N NaOH (0.3 mL, 0.3 mmol)
in 1,4-dioxane (10 mL) and EtOH (6 mL) at room temperature
for 6 h. The organics were removed in vacuo; the residue was
diluted with water and acidified to pH 3 with 10% citric acid.
The solid was collected by filtration, dried in vacuo and
crystallized from 1,4-dioxane/water to provide the acid 93 (0.11
g, 90%): mp 109-111 °C; 1H NMR (300 MHz, DMSO-d6) δ
2.14 (m, 2 H), 2.33 (m, 4 H), 2.45 (m, 2 H), 4.43 (s, 2 H), 5.30
(s, 4 H), 6.97 (d, J ) 9 Hz, 4 H), 7.25 (d, J ) 9 Hz, 4 H), 7.63
(m, 4 H), 7.78 (m, 2 H), 8.00 (m, 4 H), 8.40 (d, J ) 8 Hz, 2 H);
MS (AP-CI) m/z 638 (M + H)+. Anal. Calcd for C40H35N3O5‚
0.75H2O: C, 73.77; H, 5.64; N, 6.45. Found: C, 73.77; H, 5.54;
N, 6.17.
Rep r esen ta tive P r oced u r es for Sch em e 9. 4,4-Bis(3-
ch lor o-4-(2-qu in olylm eth oxy)ph en yl)pen tan oic Acid (110).
A mixture of 4,4-bis(4-hydroxyphenyl)pentanoic acid (23) (5.72
g, 20 mmol) and N-chlorosuccinimide (5.84 g, 44 mmol) in
CHCl3 (120 mL) and 1,4-dioxane (30 mL) was refluxed for 5
h. The reaction mixture was concentrated in vacuo, the residue
was dissolved in MeOH (100 mL), cooled to -70 °C and SOCl2
(3 mL) was added, and the mixture was left at ambient
temperature for 16 h. The methanol was removed in vacuo
and this crude ester in DMF (150 mL) was treated with K2-
CO3 (13.8 g, 100 mmol) and 2-chloromethylquinoline-HCl (9
g, 42 mmol). The resulting mixture was stirred at room
temperature for 10 h, diluted with water (400 mL) and
extracted with ethyl acetate. The organic layer was washed
with water and brine, dried with MgSO4 and concentrated in
vacuo. The residue was chromatographed (silica gel, 15:1 CH2-
Cl2-EtOAc) to afford 4,4-bis(3-chloro-4-(2-quinolylmethoxy)-
phenyl)pentanoic acid methyl ester (109) (8 g, 61%) and the
byproduct 4-(3-chloro-4-(2-quinolylmethoxy)phenyl)-4-(3,5-
dichloro-4-(2-quinolylmethoxy)phenyl)pentanoic acid methyl
ester (1.2 g, 9%).
To a solution of the ester 109 (6.5 g, 10 mmol) in 1,4-dioxane
(50 mL) and MeOH (30 mL) was added 1 N NaOH (12 mL)
and the mixture was stirred at room temperature for 10 h.
The organics were removed in vacuo, the residue was diluted
with water (100 mL) and acidified to pH 3, and the precipitated
solid was collected by filtration, washed with water and dried
in vacuo. Recrystallization from CH2Cl2-hexanes provided the
acid 110 (4.8 g, 75%): mp 91-94 °C; 1H NMR (300 MHz,
DMSO-d6) δ 1.53 (s, 3 H), 1.96 (m, 2 H), 2,30 (m, 2 H), 5.44 (s,
4 H), 7.09 (dd, J ) 3 Hz, 9 Hz, 2 H), 7.20 (d, J ) 9 Hz, 2 H),
7.24 (d, J ) 3 Hz, 2 H), 7.62 (m, 2 H), 7.71 (d, J ) 9 Hz, 2 H),
7.80 (m, 2 H), 8.00 (m, 4 H), 8.44 (d, J ) 9 Hz, 2 H), 12.08 (bs,
1 H); MS (DCI-NH3) m/z 637 (M + H)+. Anal. Calcd for C37H30
-
Cl2N2O4‚H2O: C, 67.79; H, 4.92; N, 4.27. Found: C, 68.02; H,
4.85; N, 3.94.
Biologica l Meth od s. Percent inhibition was computed by
comparing individual values in treatment groups to the mean
value of the control group. Statistical significance was deter-
mined using one-way analysis of variance and Tukeys multiple
comparison procedure. Linear regression was used to estimate
IC50 and ED50 values.
Hu m a n Neu tr op h il Leu k otr ien e Biosyn th esis Assa y.15
Heparinized blood samples were collected and layered over
Ficoll-Hypaque Mono-Poly Resolving Media (Flow Lab, McLean,
VA) and centrifuged at 300g for 30 min. The polymorpho-
nuclear leukocyte (neutrophil) layer was removed, subjected
to brief hypotonic lysis to remove red blood cell contamination,
and washed three times. Aliquots of the neutrophil suspension
were incubated with test compounds and leukotriene biosyn-
thesis was stimulated by addition of calcium ionophore A-23187.
Incubations were extracted with 4 volumes of methanol and
LTB4 was measured by enzyme immunoassay.
Ra t P leu r a l In fla m m a tion Mod el.16 Rats were dosed with
experimental compounds in 0.2% HPMC 1 h before the
intrapleural injection of the calcium ionophore A-23187. The
rats were lightly anesthetized with penthrane and injected
intrapleurally with 0.5 mL of 2% ethanol in injectable saline
containing 20 µg of A-23187. Thirty minutes later, the rats
were killed, and the pleural cavities were lavaged with ice-
cold saline. The lavage fluid was then added to ice-cold
methanol (final methanol concentration, 30%) to lyase cells
and precipitate protein. Leukotrienes were determined by
enzyme immunoassay.
Ra t P er iton ea l An a p h yla xis Mod el.15 Rats were pas-
sively sensitized to bovine serum albumin, and 3 h later they
were challenged in the peritoneal cavity with antigen. The
peritoneal cavity was lavaged 15 min later, and the fluids were
analyzed for leukotriene content by enzyme immunoassay.
Lu n g In fla m m a tion Mod el.19 Brown Norway rats were
Repr esen tative P r ocedu r es for Sch em e 8. 4-(4-(2-Ben zo-
thiazolylmethoxy)phenyl)-4-(4′-(2-quinolylmethoxy)phenyl)penta-
n oic Acid (104). To a solution of 31 (4.09 g, 13.6 mmol) and
K2CO3 (3.96 g, 28.6 mmol) in DMF (50 mL) was added
2-chloromethylquinoline-HCl (2.92 g, 13.6 mmol) and the
mixture was stirred for 48 h. The mixture was diluted with
water and acidified to pH 3 with 10% citric acid. The resulting
mixture was extracted twice with EtOAc; the extracts were
combined and washed with water and brine, dried over MgSO4
and concentrated in vacuo. The residue was purified by
chromatography (silica gel, 2:1 hexanes-EtOAc) to give 4-(4-
hydroxyphenyl)-4-(4′-(2-quinolylmethoxy)phenyl)pentanoic acid
methyl ester (100) (1.54 g, 36%).
A solution of 100 (1.54 g, 3.5 mmol) and K2CO3 (0.677 g,
4.9 mmol) in DMF (25 mL) was treated with 2-chloromethyl-
benzothiazole (0.64 g, 3.5 mmol) for 48 h at room temperature.
Water was added and the product was extracted with EtOAc.
The organic layer was washed with water and brine, dried over
MgSO4 and concentrated in vacuo. The residue was purified
by chromatography (silica gel, 19:1 CH2Cl2-EtOAc) to give 4-(4-
(2-benzothiazolylmethoxy)phenyl)-4-(4′-(2-quinolylmethoxy)-
phenyl)pentanoic acid methyl ester (101) (0.670 g, 33%).
To a solution of 101 (0.650 g, 1.1 mmol) in MeOH:1,4-
dioxane (10:1) was added 1 N NaOH (1.38 mL, 1.38 mmol)
and the resulting solution was stirred for 12 h at room
temperature, followed by refluxing for 48 h to complete the
hydrolysis. The organic solvents were removed in vacuo and
the residue was diluted with water. The resulting solution was
acidified with 10% citric acid to pH 3 and the precipitated solid
was collected by filtration, washed with water and hexane to
1
provide the acid 104 (0.625 g, 97%): mp 68-72 °C; H NMR
(300 MHz, DMSO-d6) δ 1.52 (s, 3 H), 1.94 (m, 2 H), 2.27 (m, 2
H), 5.33 (s, 2 H), 5.56 (s, 2 H), 7.00 (m, 4 H), 7.11 (m, 4 H),
7.46 (m, 1 H), 7.53 (m, 1 H), 7.62 (m, 1 H), 7.67 (d, J ) 9 Hz,

3334 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
Kolasa et al.
of Inhibitors of Leukotriene Biosynthesis and Their Therapeutic
Potential. Pure Appl. Chem. 1998, 70, 271-274. (b) Kolasa, T.;
Bhatia, P.; Brooks, C. D. W.; Hulkower, K. I.; Bouska, J . B.;
Harris, R. R.; Bell, R. L. Synthesis of Indolylalkoxyiminoalky-
lcarboxylates as Leukotriene Biosynthesis Inhibitors. Bioorg.
Med. Chem. 1997, 5, 507-514. (c) Woods, K. W.; Brooks, C. D.
W.; Maki, R. G.; Rodriques, K, E.; Bouska, J . B.; Young, P.; Bell,
R. L.; Carter, G. W. O-Alkylcarboxylate Oxime and N-Hy-
droxyurea Analogues of Substituted Indole Leukotriene Biosyn-
thesis Inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 1547-1552.
(9) Kolasa, T.; Gunn, D. E.; Bhatia, P.; Craig, R. A.; Woods, K. W.;
Gane, T.; Bouska, J . B.; Harris, R. R.; Hulkover, K. I.; Malo, P.
E.; Bell, R. L.; Carter, G. W., Brooks, C. D. W. Heteroaryl-
methoxyphenylalkoxyiminoalkylcarboxylic Acids as Leukotriene
Biosynthesis Inhibitors. J . Med. Chem. 2000, 43, 690-705.
(10) Mitsunobu, O. The Use of Diethyl Azodicarboxylate and Tri-
phenylphosphine in Synthesis and Transformation of Natural
Products. Synthesis 1981, 1-28.
orally dosed with inhibitors in 0.2% methylcellulose and then
injected in the central tail vein with Sephadex G-200. For the
next 3 days, the rats were dosed either once or twice a day
with either inhibitor or the vehicle control, 0.2% methylcel-
lulose. The rats were anesthetized, and the airways were
lavaged with phosphate-buffered saline and analyzed for
leukotriene content by enzyme immunoassay.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for the compounds shown in the
tables that are not described here. This material is available
free of charge via the Internet at http://pubs.acs.org.
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J M000180N